Method of treating migraine headaches with a highly selective noreoinephrine reuptake inhibitor

ABSTRACT

Methods for treating humans suffering from, migraine headaches by inhibiting reuptake of norepinephrine are disclosed. The methods comprise a compound having a pharmacological selectivity of serotonin (K i )/norepinephrine (K i ) of at least about 5000. Examples of such compounds include reboxetine, and more preferably optically pure (S,S) enantiomer of reboxetine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of U.S. patent application Ser. No. 09/599,213 filedJun. 22, 2000, now U.S. Pat. No. 6,465,458 issued Oct. 15, 2002, whichclaims the benefit under 35 U.S.C. §119(e) of U.S. provisional patentapplication Ser. No. 60/141,968 filed Jul. 1, 1999, U.S. provisionalpatent application Ser. No. 60/144,131 filed Jul. 16, 1999, U.S.provisional patent application Ser.. No. 60/158,256 filed Oct. 6, 1999,and U.S. provisional patent application Ser. No. 60/170,381 filed Dec.13, 1999, the disclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods of treating individualssuffering from a variety of conditions wherein inhibiting reuptake ofnorepinephrine provides a benefit. In particular, the present inventionrelates to methods of treatment comprising administration of a compound,such as (S,S) reboxetine, to an individual, wherein the compound has ahigh pharmacological selectivity with respect to norepinephrine reuptakesites compared to serotonin reuptake sites. The present invention alsorelates to a composition containing the compound and to a preparation ofa medicament containing the composition.

2. Brief Description of Related Technology

Many types of depression, mental, behavioral, and neurological disordersoriginate from disturbances in brain circuits that convey signals usingcertain monoamine neurotransmitters. Monoamine neurotransmittersinclude, for example, norepinephrine (noradrenaline), serotonin (5-HT),and dopamine. Lower-than-normal levels of norepinephrine are associatedwith a variety of symptoms including lack of energy, motivation, andinterest in life. Thus, a normal level of norepinephrine is essential tomaintaining drive and capacity for reward.

These neurotransmitters travel from the terminal of a neuron across asmall gap (i.e., the synaptic cleft) and bind to receptor molecules onthe surface of a second neuron. This binding elicits intracellularchanges that initiate or activate a response or change in thepostsynaptic neuron. Inactivation occurs primarily by transport (i.e.,reuptake) of the neurotransmitter back into the presynaptic neuron.Abnormality in noradrenergic transmission results in various types ofdepression, mental, behavioral, and neurological disorders attributed toa variety of symptoms including a lack of energy, motivation, andinterest in life. See generally, R. J. Baldessarini, “Drugs and theTreatment of Psychiatric Disorders: Depression and Mania” in Goodman andGilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, NY, NY,pp. 432-439 (1996).

Reboxetine (i.e., 2-[(2-ethoxyphenoxy)(phenyl)methyl] morpholine) raisesthe concentration of physiologically active norepinephrine by preventingreuptake of norepinephrine, for example. Reboxetine is a norepinephrinereuptake inhibitor and has been shown to be effective in the short-term(i.e., less than eight weeks) and long-term treatment of depression. Infact, reboxetine has been shown to have effectiveness that is similar tofluoxetine, imipramine, and desipramine, commonly prescribedantidepressants, in both adults and elderly patients. See S. A.Montgomery, Reboxetine: Additional Benefits to the Depressed Patient,Psychopharmocol (Oxf) 11:4 Suppl., S9-15 (Abstract) (1997).

Antidepressant drugs are sometimes divided into “generations.” The firstgeneration included the monoamine oxidase inhibitors (such asisocarboxazid and phenylhydrazine) and tricyclic agents (such asimipramine). The second generation of antidepressant drugs includedcompounds such as mianserin and trazodone. The third generation hasincluded drugs called selective reuptake inhibitors (e.g., fluoxetine,sertraline, paroxetine, and reboxetine). Those drugs were characterizedby relatively selective action on only one of the three main monoaminesystems thought to be involved in depression (i.e., 5-HT (serotonin),noradrenaline (norepinephrine), and dopamine). APP Textbook ofPsychopharmacology (A. F. Schatzberg and C. B. Nemeroff), AmericanPsychiatric Press, 2d. ed., (1998); Lexicon of Psychiatry, Nuerology andthe Neurosciences (F. J. Ayd, Jr.) Williams and Wilkins (1995). Theantidepressant efficacy of reboxetine is evidenced by its ability toprevent resperine-induced blepharospasm and hypothermia in mice, downregulation of β-adrenergic receptors and desensitization ofnoradrenaline-coupled adenylate cyclase. See M. Brunello and G. Racagni,“Rationale for the Development of Noradrenaline Reuptake Inhibitors,”Human Psychophramacology, vol. 13, S-13-519, Supp. 13-519 (1998).

According to a survey by Brian E. Leonard, desipramine, maprotiline, andlofepramine are relatively selective norepinephrine reuptake inhibitorswith proven efficacy. These materials increase brain noradrenaline andthereby function to relieve depression. Mianserin and mirtazepine alsoshow antidepressant-like effects by increasing noradrenalineavailability by means of blocking the pre-synaptic α₂-adrenoceptors.Still further, oxaprotiline, fezolamine, and tomoxetine are potent andselective norepinephrine reuptake inhibitors that lack neurotransmitterreceptor interactions and, thus, do not cause many of the side effectscharacteristic of classical tricyclic antidepressants. See Brian E.Leonard, “The Role of Noradrenaline in Depression: A Review,” Journal ofPsychopharmocology, vol. 11, no. 4 (Suppl.), pp. S39-S47 (1997)

Reboxetine also is a selective norepinephrine reuptake inhibitor, whichalso produces fewer of the side effects associated with theadministration of classical tricyclic antidepressants. Theantidepressant efficacy of reboxetine is evidenced by its ability toprevent resperine-induced blepharospasm and hypothermia in mice, downregulation of β-adrenergic receptors and desensitization ofnoradrenaline-coupled adenylate cyclase. See M. Brunello and G. Racagni,“Rationale for the Development of Noradrenaline Reuptake Inhibitors,”Human Psychophramacology, vol. 13 (Supp.) 13-519 (1998).

Reboxetine generally is described in Melloni et al. U.S. Pat. Nos.4,229,449, 5,068,433, and 5,391,735, and in GB 2,167,407, thedisclosures of which are hereby incorporated by reference. Chemically,reboxetine has two chiral centers and, therefore, exists as twoenantiomeric pairs of diastereomers, shown below as isomers (I) through(IV):

Many organic compounds exist in optically active forms, i e., they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound the prefixes R and S are used to denote theabsolute configuration of the molecule about its chiral center(s). Theprefixes D and L, or (+) or (−), designate the sign of rotation ofplane-polarized light by the compound, with L or (−) meaning that thecompound is levorotatory. In contrast, a compound prefixed with D or (+)is dextrorotatory. There is no correlation between nomenclature for theabsolute stereochemistry and for the rotation of an enantiomer. Thus,D-lactic acid is the same as (−)-lactic acid, and L-lactic acid is thesame as (+)-lactic acid. For a given chemical structure, each of a pairof enantiomers are identical except that they are non-superimposablemirror images of one another. A specific stereoisomer may also bereferred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric, or racemic, mixture.

Stereochemical purity is important in the pharmaceutical field, wheremany of the most often prescribed drugs exhibit chirality. For example,the L-enantiomer of the beta-adrenergic blocking agent, propranolol, isknown to be 100 times more potent than its D-enantiomer. Additionally,optical purity is important in the pharmaceutical drug field becausecertain isomers have been found to impart a deleterious effect, ratherthan an advantageous or inert effect. For example, it is believed thatthe D-enantiomer of thalidomide is a safe and effective sedative whenprescribed for the control of morning sickness during pregnancy, whereasits corresponding L-enantiomer is believed to be a potent teratogen.

When two chiral centers exist in one molecule, there are four possiblestereoisomers: (R,R), (S,S), (R,S), and (S,R). Of these, (R,R) and (S,S)are an example of a pair of enantiomers (mirror images of each other),which typically share chemical properties and melting points just likeany other enantiomeric pair. The mirror images of (R,R) and (S,S) arenot, however, superimposable on (R,S) and (S,R). This relationship iscalled diastereoisomeric, and the (S,S) molecule is a diastereoisomer ofthe (R,S) molecule, whereas the (R,R) molecule is a diastereoisomer ofthe (S,R) molecule.

Currently, reboxetine is commercially available only as a racemicmixture of enantiomers, (R,R) and (S,S) in a 1:1 ratio, and referenceherein to the generic name “reboxetine” refers to this enantiomeric, orracemic, mixture. Reboxetine is commercially sold under the trade namesof EDRONAX™, PROLIFT™, VESTRA™, and NOREBOX™. As previously noted,reboxetine has been shown to be useful in the treatment of humandepression. Orally administered reboxetine is readily absorbed andrequires once or twice a day administration. A preferred adult dailydose is in the range of about 8 to about 10 milligrams (mg). Theeffective daily dosage of reboxetine for a child is smaller, typicallyin a range of about 4 to about 5 mg. The optimum daily dosage for eachpatient, however, must be determined by a treating physician taking intoaccount the patient's size, other medications which the patient may betaking, identity and severity of the particular disorder, and all of theother circumstances of the patient.

Administration of reboxetine, however, can result in undesired sideeffects associated with drug-drug interactions and in other undesirableeffects such as, for example, dizziness, insomnia, lightheadedness,changes in blood pressure, sweating, gastrointestinal disturbances,sexual dysfunction in males, certain anticholinergic-like effects (e.g.,tachyardia and urinary retention). It has been found that such sideeffects occur, in part, because reboxetine lacks a sufficiently highselectivity for inhibiting norepinephrine reuptake. In other words,reboxetine is blocking reuptake of other monoamines, like serotonin anddopamine, to a sufficient degree to contribute to the undesired sideeffects.

It has been reported that other antidepressants have a highpharmacological selectivity for inhibiting reuptake of norepinephrine.For example, oxaprotiline has a pharmacological selectivity with respectto inhibiting norepinephrine reuptake compared to serotonin reuptake ofabout 4166, based on a ratio of K_(i) values. The correspondingpharmacological selectivity for desipramine is about 377, and that formaprotiline is about 446. See Elliott Richelson and Michael Pfenning,“Blockade by Antidepressants and Related Compounds of Biogenic AmineUptake in Rat Brain Synaptosomes: Most Antidepressants Selectively BlockNorepinephrine Uptake,” European Journal of Pharmacology, vol.14, pp.277-286 (1984). Despite the relatively high selectivity of oxaprotiline,desipramine, and maprotiline, these and other known materialsundesirably block receptor of other neurotransmitters to a sufficientdegree that they also contribute to adverse side effects.

Accordingly, there is a need in the art for a method of treatingindividuals suffering from a variety of conditions where inhibitingreuptake of norepinephrine provides a benefit, while reducing oreliminating the adverse side effects associated with conventionalnorepinephrine reuptake inhibitors. There also is a need for a methodthat selectively inhibits the reuptake of norepinephrine over otherneurotransmitters, like serotonin and dopamine. Specifically, there is aneed in the art for a highly selective (at one reuptake site), specific(with no activity at other receptors), and potent norepinephrinereuptake inhibitor. Furthermore, there is a need for pharmaceuticalcompositions containing a highly selective and potent norepinephrinereuptake inhibitor. Still further, there is a need for medicamentscontaining such pharmaceutical compositions, and the use of suchcompositions in the manufacture of such medicaments.

SUMMARY OF THE INVENTION

The present invention generally is directed to compositions and methodsof treating or preventing a variety of human conditions where inhibitionof norepinephrine reuptake provides a benefit and, more specifically,where selective, specific, and potent inhibition of norepinephrineprovides a benefit. More particularly, the present invention is directedto an effective treatment or prevention of such conditions comprisingadministration of compounds, such as reboxetine or an optically pure(S,S) stereoisomer thereof, to a human.

Accordingly, one embodiment of the present invention is directed to amethod of selectively inhibiting reuptake of norepinephrine, the methodcomprising the step of administering a therapeutically effective amountof a composition to an individual, the composition comprising a compoundhaving a pharmacological selectivity of serotonin (K_(i))/norepinephrine(K_(i)) of at least about 5000, preferably at least about 10,000, andmore preferably at least about 12,000.

Another embodiment of the present invention is directed to a method oftreating a human suffering from a condition, or preventing saidcondition, wherein inhibiting reuptake of norepinephrine provides abenefit, the method comprising the step of administering atherapeutically effective amount of a composition comprising a compoundhaving a pharmacological selectivity of serotonin (K_(i))/norepinephrine(K_(i)) of at least about 5000, preferably at least about 10,000, andmore preferably at least about 12,000.

Another embodiment of the present invention is directed to a preparationof a medicament from a composition comprising a compound having apharmacological selectivity of serotonin (K_(i))/norepinephrine (K_(i))of at least about 5000, preferably at least about 10,000, and morepreferably at least about 12,000 to treat or prevent at least onenervous system disorder selected from the group consisting of addictivedisorders (including those due to alcohol, nicotine, and otherpsychoactive substances) and withdrawal syndrome, adjustment disorders(including depressed mood, anxiety, mixed anxiety and depressed mood,disturbance of conduct, and mixed disturbance of conduct and mood),age-associated learning and mental disorders (including Alzheimer'sdisease), anorexia nervosa, apathy, attention-deficit (or othercognitive) disorders due to general medical conditions,attention-deficit hyperactivity disorder (ADHD), bipolar disorder,bulimia nervosa, chronic fatigue syndrome, chronic or acute stress,chronic pain, conduct disorder, cyclothymic disorder, depression(including adolescent depression and minor depression), dysthymicdisorder, fibromyalgia and other somatoform disorders (includingsomatization disorder, conversion disorder, pain disorder,hypochondriasis, body dysmorphic disorder, undifferentiated somatoformdisorder, and somatoform NOS), generalized anxiety disorder (GAD),incontinence (i.e., stress incontinence, genuine stress incontinence,and mixed incontinence), inhalation disorders, intoxication disorders(alcohol addiction), mania, migraine headaches, obesity (i.e., reducingthe weight of obese or overweight patients), obsessive compulsivedisorders and related spectrum disorders, oppositional defiant disorder,panic disorder, peripheral neuropathy, post-traumatic stress disorder,premenstrual dysphoric disorder (i.e., premenstrual syndrome and lateluteal phase dysphoric disorder), psychotic disorders (includingschizophrenia, schizoaffective and schizophreniform disorders), seasonalaffective disorder, sleep disorders (such as narcolepsy and enuresis),social phobia (including social anxiety disorder), specificdevelopmental disorders, selective serotonin reuptake inhibition (SSRI)“poop out” syndrome (i.e., wherein a patient who fails to maintain asatisfactory response to SSRI therapy after an initial period ofsatisfactory response), and TIC disorders (e.g., Tourette's Disease).

Another embodiment of the present invention is directed to use of acomposition comprising a compound having a pharmacological selectivityof serotonin (K_(i))/norepinephrine (K_(i)) of at least about 5000,preferably at least about 10,000, and more preferably at least about12,000, in a manufacture of a medicament to treat or prevent at leastone of the aforementioned nervous system disorders.

An example of a compound having a pharmacological selectivity ofserotonin (K_(i))/norepinephrine (K_(i)) of at least about 5000, isoptically pure (S,S) reboxetine substantially free of its (R,R)stereoisomer. Individuals treated with optically pure (S,S) reboxetinedo not experience certain adverse side effects associated with theadministration of the racemic mixture of (R,R) and (S,S) reboxetine. Thepresent invention therefore includes administering optically pure (S,S)reboxetine to a human to selectively inhibit norepinephrine reuptake,and thereby control, reduce, or eliminate adverse effects caused by theadministration of the racemic mixture of reboxetine.

More specifically, another embodiment of the present invention isdirected to a method of treating or preventing a human condition whereininhibiting reuptake of norepinephrine provides a benefit. The methodcomprises the step of administering a therapeutic amount, typicallyabout 0.5 to about 10 mg/day, of optically pure (S,S) reboxetine, or apharmaceutically acceptable salt thereof. Optically pure (S,S)reboxetine is substantially free of (R,R) reboxetine.

Optically pure (S,S) reboxetine is advantageous over prior treatment orprevention methods which utilized a racemic mixture of (R,R) and (S,S)reboxetine. In particular, it has been found that treatments usingcompositions containing an optically pure (S,S) reboxetine are about 5to about 8.5 times more effective at inhibiting the reuptake ofnorepinephrine than compositions containing the racemic mixture of the(R,R) and (S,S) stereoisomers. Therefore, reuptake blockage can beachieved with much lower dosages. Accordingly, the present invention maypermit a substantial reduction in the customary daily dosage of theracemic mixture (i.e., the commercially available reboxetine) by about50% to about 80% because of the use of an optically pure (S,S)reboxetine. In addition, treatments utilizing the optically pure (S,S)reboxetine may result in fewer undesirable adverse side effectsassociated with the treatment because of the high selectivity andpotency of (S,S) reboxetine with respect to inhibiting the reuptake ofnorepinephrine.

Another embodiment of the present invention is directed to a method oftreating or preventing a nervous system disorder comprising the step ofadministering a therapeutically effective dose of racemic reboxetine toan individual, wherein the disorder is at least one of an adjustmentdisorder, an age-associated learning and mental disorder, anorexianervosa, apathy, an attention-deficit disorder due to general medicalconditions, bipolar disorder, bulimia nervosa, chronic fatigue syndrome,chronic or acute stress, chronic pain, cyclothymic disorder, dysthymicdisorder, fibromyalgia and other somatoform disorders, incontinence,mania, migraine headaches, obesity, peripheral neuropathy,post-traumatic stress disorder, premenstrual dysphoric disorder, apsychotic disorder, seasonal affective disorder, a sleep disorders, aspecific developmental disorders, SSRI “poop out” syndrome, and TICdisorders. Other embodiments of the present invention are directed to apreparation of a medicament from a composition comprising reboxetine anda use of reboxetine in a manufacture of the medicament to treat orprevent at least one of the aforementioned nervous system disorders.

Additional benefits and features of the present invention will becomeapparent to those skilled in the art from a review of the followingdetailed description, taken in conjunction with the example and theappended claims. It should be noted, however, that while the inventionis susceptible of embodiments in various forms, described hereafter arespecific preferred embodiments of the invention with the understandingthat the present disclosure is intended as illustrative, and is notintended to limit the invention to the specific embodiments describedherein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reboxetine is a known compound that is active on the central nervoussystem, and has been used as an antidepressant. Heretofore, use ofreboxetine has been limited to the treatment of depression, oppositionaldefiant disorder, attention-deficit/hyperactivity disorder, and conductdisorder. These proposed treatments are disclosed in InternationalPublication Nos. WO 99/15163, WO 95/15176, and WO 99/15177. Thesetreatment methods are limited to administration of a racemic mixture ofthe (S,S) and (R,R) reboxetine stereoisomers.

Reboxetine does not act like most antidepressants. Unlike tricyclicantidepressants, and even selective serotonin reuptake inhibitors(SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test,indicating that reboxetine is not a SSRI. Brian E. Leonard,“Noradrenaline in basic models of depression.”European-Neuropsychopharmacol, 7 Suppl. 1 pp. S 11-6 and S71-3 (April1997). Reboxetine is a selective norepinephrine reuptake inhibitor, withonly marginal serotonin and no dopamine reuptake inhibitory activity.Reboxetine displays no anticholinergic binding activity in differentanimal models, and is substantially devoid of monoamine oxidase (MAO)inhibitory activity. Racemic reboxetine exhibits a pharmacologicalselectivity of serotonin (K_(i))/norepinephrine (K_(i)) of about 80. TheK_(i) values are discussed in more detail hereafter.

Another embodiment of the present invention includes a method ofselectively inhibiting reuptake of norepinephrine, the method comprisingthe step of administering a therapeutically effective amount of acomposition to an individual, the composition comprising a compoundhaving a pharmacological selectivity of serotonin (K_(i))/norepinephrine(K_(i)) of at least about 5000, preferably at least about 10,000, andmore preferably at least about 12,000.

Another embodiment of the present invention is directed to a compositioncomprising a compound having a pharmacological selectivity of serotonin(K_(i))/norepinephrine (K_(i)) of at least about 5000, preferably atleast about 10,000, and more preferably at least about 12,000. Theinventive composition is useful in the treatment or prevention ofdiseases, disorders, and conditions (described in more detail below)wherein inhibition of reuptake of norepinephrine is beneficial. Anexample of such a compound is an optically pure (S,S) stereoisomer ofreboxetine, or a pharmaceutically effective salt thereof.

To determine the degree of selectivity of a compound to bind to thenorepinephrine reuptake site, the inhibition constant (or K_(i) value)of the compound for serotonin reuptake site was divided by the K_(i)value for norepinephrine reuptake site. A lower value of K_(i) fornorepinephrine reuptake indicates greater binding affinity tonorepinephrine receptors. A higher serotonin (K_(i))/norepinephrine(K_(i)) ratio indicates a greater selectivity for binding thenorepinephrine receptor. Accordingly, the present invention is directedto a composition comprising a compound having a pharmacologicalselectivity of serotonin (K_(i))/norepinephrine (K_(i)) of at leastabout 5000, preferably at least about 10,000, and more preferably atleast about 12,000, as noted above. Furthermore, it is envisioned thatselectivity values far in excess of 12,000, such as 25,000, 50,000,75,000, and even up to 100,000 or greater, also are beneficial.

The compositions of the present invention, when employed in effectiveamounts in accordance with the present invention, are selective withrespect to the norepinephrine reuptake site, but do not causesignificant blockade of receptors associated with undesirable sideeffects e.g., serotonin and dopamine receptors. In other words, a doseof the inventive composition capable of inhibiting the reuptake ofnorepinephrine, is essentially ineffective in eliciting blockade ofother neurotransmitter receptors. Inhibition constants (K_(i) values),typically reported in units of nanamolars (nM), were calculated from theIC₅₀ values according to the method set forth in Y. C. Cheng and W. H.Prusoff, “Relationship Between the Inhibitory Constant (K_(i)) and theConcentration of Inhibitor Which Causes 50% Inhibition (IC₅₀) of anEnzymatic Reaction,” Biochemical Pharmacology, vol. 22, pp. 3099-3108(1973).

Another embodiment of the present invention is directed to an effectivemethod using an optically pure (S,S) stereoisomer of reboxetine to treator prevent conditions wherein inhibition of reuptake of norepinephrineis beneficial. (S,S) Reboxetine is an effective, selective inhibitor ofnorepinephrine reuptake and, accordingly, dose levels can besubstantially reduced in comparison to racemic reboxetine. In addition,individuals treated with an optically pure (S,S) reboxetine do notexperience certain adverse effects associated with the administration ofthe racemic mixture of (R,R) and (S,S) reboxetine. Accordingly, anotherembodiment of the present invention includes administering a therapeuticamount of an optically pure (S,S) reboxetine to a human to inhibit thereuptake of norepinephrine, and to control, reduce, or eliminate adverseeffects associated with administration of racemic reboxetine.

Yet another embodiment of the present invention is directed to a methodof treating or preventing a human condition wherein inhibiting reuptakeof norepinephrine provides a benefit. The method comprises the step ofadministering, and preferably orally administering, a total dose ofabout 0.1 mg/day to about 10 mg/day, more preferably about 0.5 to about10 mg/day of an optically pure (S,S) reboxetine, or a pharmaceuticallyacceptable salt thereof, to an individual.

As used herein, the term “reboxetine” refers to the racemic mixture ofthe (R,R) and (S,S) enantiomers of reboxetine. In contrast, the term“(S,S) reboxetine” refers to only the (S,S) stereoisomer. Similarly, theterm “(R,R) reboxetine” refers to only the (R,R) stereoisomer.

The phrases “optically pure (S,S) reboxetine” and “substantially free ofits (R,R) stereoisomer,” as used herein, mean that the compositioncontains a greater proportion of (S,S) reboxetine in relation to (R,R)reboxetine. In a preferred embodiment, the phrases mean that thecomposition is at least 90 percent by weight (wt. %) of (S,S)reboxetine, and 10 wt. % or less of (R,R) reboxetine. In a morepreferred embodiment the phrases mean that the composition contains atleast 97 wt. % of (S,S) reboxetine, and 3 wt. % or less of (R,R)reboxetine. In an even more preferred embodiment, the phrases mean thatthe composition contains at least 99 wt. % of (S,S) reboxetine, and 1wt. % or less of (R,R) reboxetine. In a most preferred embodiment, thephrases “optically pure (S,S) reboxetine” and “substantially free of its(R,R) stereoisomer,” as used herein, mean that the composition containsgreater than 99 wt. % of (S,S) reboxetine. The foregoing percentages arebased upon the total amount of reboxetine present in the composition.The phrases “substantially free of (R,R) reboxetine,” “substantiallyoptically pure (S,S) stereoisomer of reboxetine,” “substantiallyoptically pure (S,S) reboxetine,” “optically pure (S,S) stereoisomer ofreboxetine,” and “optically pure (S,S) reboxetine” are also encompassedby the above-described amounts.

The phrases “pharmaceutically acceptable salts” or “a pharmaceuticallyacceptable salt thereof” refer to salts prepared from pharmaceuticallyacceptable acids or bases, including organic and inorganic acids andbases. Because the active compound (i.e., (S,S) reboxetine) used in thepresent invention is basic, salts may be prepared from pharmaceuticallyacceptable acids. Suitable pharmaceutically acceptable acids includeacetic, benzenesulfonic (besylate), benzoic, p-bromophenylsulfonic,camphorsulfonic, carbonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic,maleic, malic, mandelic, methanesulfonic (mesylate), mucic, nitric,oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic, and the like. Examples of such pharmaceuticallyacceptable salts of (S,S) reboxetine, thus, include, but are not limitedto, acetate, benzoate, β-hydroxybutyrate, bisulfate, bisulfite, bromide,butyne-1,4-dioate, carpoate, chloride, chlorobenzoate, citrate,dihydrogenphosphate, dinitrobenzoate, fumarate, glycollate, heptanoate,hexyne-1,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate,mandelate, metaphosphate, methanesulfonate, methoxybenzoate,methylbenzoate, monohydrogenphosphate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, oxalate, phenylbutyrate, phenylproionate,phosphate, phthalate, phylacetate, propanesulfonate, propiolate,propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate,sulfate, sulfite, sulfonate, tartrate, xylenesulfonate, and the like. Apreferred pharmaceutical salt of (S,S) reboxetine is methanesulfonate(i.e., mesylate), which is prepared using methanesulfonic acid.

The phrases “side effects,” “adverse effects,” and “adverse sideeffects” in relation to reboxetine include, but are not limited to,dizziness, insomnia, lightheadedness, changes in blood pressure,gastrointestinal disturbances, sexual dysfunction in males,extrapyramidal side effects, certain anticholinergic-like effects (e.g.,tachycardia, blurred vision), and undesired side effects associated withwith drug-drug interactions.

As used herein, the terms “treat,” “treatment,” and “treating,” referto: (a) preventing a disease, disorder, or condition from occurring in ahuman which may be predisposed to the disease, disorder and/or conditionbut has not yet been diagnosed as having it; (b) inhibiting the disease,disorder, or condition, i.e., arresting its development; and (c)relieving the disease, disorder, or condition, i.e., causing regressionof the disease, disorder and/or condition. In other words, the terms“treat,” “treatment,” and “treating,” extend to prophylaxis, in otherwords “prevent,” “prevention,” and “preventing,” as well as treatment ofestablished conditions. Accordingly, use of the terms “prevent,”“prevention,” and “preventing,” would be an administration of thepharmaceutical composition to a person who has in the past suffered fromthe aforementioned conditions, such as, for example, migraine headaches,but is not suffering from the conditions at the moment of thecomposition's administration. For the sake of simplicity, the term“conditions” as used hereinafter encompasses conditions, diseases, anddisorders.

Methods and compositions of the present invention are useful in treatinga human condition wherein inhibiting reuptake of norepinephrine providesa benefit. The method comprises the step of administering, andpreferably orally administering, a sufficient amount of the inventivecomposition to provide a total dose of about 0.1 to about 10 mg/day ofthe selective compound to an individual.

More specifically, administration of the inventive composition (e.g., acomposition containing an optically pure (S,S) reboxetine) is effectivein treating various human conditions including, but not limited to,addictive disorders (including those due to alcohol, nicotine, and otherpsychoactive substances) and withdrawal syndrome, adjustment disorders(including depressed mood, anxiety, mixed anxiety and depressed mood,disturbance of conduct, and mixed disturbance of conduct and mood),age-associated learning and mental disorders (including Alzheimer'sdisease), anorexia nervosa, apathy, attention-deficit (or othercognitive) disorders due to general medical conditions,attention-deficit hyperactivity disorder (ADHD), bipolar disorder,bulimia nervosa, chronic fatigue syndrome, chronic or acute stress,chronic pain, conduct disorder, cyclothymic disorder, depression(including adolescent depression and minor depression), dysthymicdisorder, fibromyalgia and other somatoforn disorders (includingsomatization disorder, conversion disorder, pain disorder,hypochondriasis, body dysmorphic disorder, undifferentiated somatoforndisorder, and somatoform NOS), generalized anxiety disorder (GAD),incontinence (i.e., stress incontinence, genuine stress incontinence,and mixed incontinence), inhalation disorders, intoxication disorders(alcohol addiction), mania, migraine headaches, obesity (i.e., reducingthe weight of obese or overweight patients), obsessive compulsivedisorders and related spectrum disorders, oppositional defiant disorder,panic disorder, peripheral neuropathy, post-traumatic stress disorder,premenstrual dysphoric disorder (i.e., premenstrual syndrome and lateluteal phase dysphoric disorder), psychotic disorders (includingschizophrenia, schizoaffective and schizophrerniform disorders),seasonal affective disorder, sleep disorders (such as narcolepsy andenuresis), social phobia (including social anxiety disorder), specificdevelopmental disorders, selective serotonin reuptake inhibition (SSRI)“poop out” syndrome (i.e., wherein a patient who fails to maintain asatisfactory response to SSRI therapy after an initial period ofsatisfactory response), and TIC disorders (e.g., Tourette's Disease).

The administration of the inventive composition is very effective in thetreatment of addictive disorders and withdrawal syndromes, adjustmentdisorders, apathy, attention-deficit hyperactivity disorder,attention-deficit disorders due to medical conditions, bulimia nervosa,chronic fatigue syndrome, chronic or acute stress, depression, dysthymicdisorder, generalized anxiety disorder (GAD), nicotine addiction, panicdisorder, post-traumatic stress disorder, premenstrual dysphoricdisorder, schizoaffective disorder, and SSRI “poop out” syndrome.Furthermore, the administration of (S,S) reboxetine is especiallyeffective in treatment or prevention of addictive disorders andwithdrawal syndromes, apathy, attention-deficit hyperactivity disorder,attention-deficit disorders due to medical conditions, chronic fatiguesyndrome, chronic or acute stress, dysthymic disorder, depression,nicotine addiction, obesity, post-traumatic stress disorder, and SSRI“poop out” syndrome.

Reference to treatments for “nicotine addiction” herein also includestreatments for smoking cessation. Many of the foregoing human conditionsare generally described by the American Psychiatric Association in theirpublication entitled, “Diagnostic and Statistical Manual of MentalDisorders,” 4th ed. rev. (Washington D.C. 1994), the disclosure of whichis hereby incorporated by reference. General descriptions of addictivedisorders, including disorders related to intoxication and inhalantsand, and nicotine addiction may be found in many standard references,such as R. E. Hales et al., “The American Psychiatric Press Textbook ofPsychiatry,” 3d. ed. (1999), the disclosure of which is herebyincorporated by reference.

An inventive composition also can be used to treat migraine headaches.Furthermore, the inventive composition can be used to treat headaches inmigraineurs or people suffering from migraine headaches, including thetreatment of symptoms of an existing headache, treatment to prevent theoccurrence, intensity, and duration of a headache, prophylactic use toprevent or reduce the incidence or duration of migraines, as an adjuvantto facilitate the effectiveness of an abortive medication orco-administered with other medications (including abortive medications)to reduce the required dosages (and side effects) of those medications.

A preferred embodiment of the inventive composition includes (S,S)reboxetine. It is known that commercially-available reboxetine is aracemic mixture of the (R,R) and (S,S) enantiomers of2-[(2-ethoxyphenoxy)(phenyl)methyl]morpholine. It has now beendiscovered that the (S,S) stereoisomer is the most active and the mostselective stereoisomer with respect to inhibiting the reuptake ofnorepinephrine. In addition, when administered to an individual, in thedosages described herein, as an optically pure material (i.e., in thesubstantial absence of its (R,R) diastereomer), the individual does notexperience many of the adverse side effects associated with theadministration of commercially-available reboxetine. Furthermore, it hasfurther been discovered that the (S,S) and (R,R) enantiomers have areversed selectivity for the norepinephrine neurotransmitter in relationto the serotonin neurotransmitter, and an optically pure (S,S)reboxetine is significantly more effective at inhibiting reuptake ofnorepinephrine than either the (R,R) enantiomer or a racemic mixture ofthe (S,S) and (R,R) enantiomers.

Specifically, it has been found that compositions containing anoptically pure (S,S) reboxetine are about 5 to about 8.5 times moreeffective at inhibiting the reuptake of norepinephrine than compositionscontaining the racemic mixture of the (R,R) and (S,S) stereoisomers.Accordingly, the typical daily dosage of the racemic mixture (i.e.,commercially available reboxetine) can be reduced by about 50% to about80% when using an optically pure (S,S) reboxetine. The reduction indosage does not lead to a reduction in efficacy, but the reduction orelimination of various adverse side effects was observed.

In particular, because an optically pure (S,S) reboxetine selectivelyinhibits norepinephrine reuptake compared to serotonin reuptake, adverseside effects associated with serotonin reuptake are reduced oreliminated. Such adverse side effects include, but are not limited to,gastrointestinal disturbances, anxiety, sexual dysfunction, andundesirable side effects associated with drug-drug interactions.

The synthesis of a racemic mixture of reboxetine is disclosed in Melloniet, al. U.S. Pat. No. 4,229,449. Individual stereoisomers of reboxetinecan be obtained by resolution of the racemic mixture of enantiomersusing conventional methods generally known by those skilled in the art.Such methods include, but are not limited to, resolution by simplecrystallization and chromatographic techniques, for example, as setforth in GB 2,167,407.

While it is possible to administer a highly selective norepinephrinereuptake inhibitor directly without any formulation, a compositionpreferably is administered in the form of pharmaceutical medicamentscomprising the selective norepinephrine reuptake inhibitor. Theinventive composition can be administered in oral unit dosage forms suchas tablets, capsules, pills, powders, or granules. The inventivecomposition also can be introduced parenterally, (e.g., subcutaneously,intravenously, or intramuscularly), using forms known in thepharmaceutical art. The inventive composition further can beadministered rectally or vaginally in such forms as suppositories orbougies. The inventive composition also can be administered topically ortransdermally, such as with a “patch” containing active ingredient.Transdermal delivery patches can be used to provide continuous,pulsatile, or on-demand infusion of the inventive compositions incontrolled amounts. The construction and use of transdermal deliverypatches are well known in the pharmaceutical art, and are described, forexample, in U.S. Pat. Nos. 3,742,951, 3,742,951, 3,797,494, 3,996,934,4,031,894, and 5,023,252.

It may be desirable or necessary to introduce the inventive compositionor pharmaceutical compositions containing the selective norepinephrinereuptake inhibitor to the brain, either directly or indirectly. Directtechniques usually involve placement of a suitable drug deliverycatheter into the ventricular system to bypass the blood-brain barrier.One such suitable delivery system used for the transport of biologicalfactors to specific anatomical regions of the body is described in U.S.Pat. No. 5,011,472, the disclosure of which is incorporated herein byreference.

In general, the preferred route of administering the inventivecomposition is oral, with a once or twice a day administration. Thedosage regimen and amount for treating patients with the inventivecomposition is selected in accordance with a variety of factorsincluding, for example, the type, age, weight, sex, and medicalcondition of the patient, the severity of the condition, the route ofadministration and the particular compound employed, either racemate orpure enantiomer. An ordinarily skilled physician or psychiatrist canreadily determine and prescribe an effective (i.e., therapeutic) amountof the compound to prevent or arrest the progress of the condition. Inso proceeding, the physician or psychiatrist could employ relatively lowdosages at first, subsequently increasing the dose until a maximumresponse is obtained.

Pharmaceutical compositions suitable for oral administration can be ofany convenient form, such as sachets, tablets, capsules, pills, oraerosol sprays, each containing a predetermined amount of the activecompound either as a powder or granules, or as a solution or asuspension in an aqueous liquid, a non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such compositions can beprepared by any method that includes the step of bringing the activecompound either into intimate association with a carrier, whichconstitutes one or more necessary or desirable ingredients. Generally,the compositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into a desiredform.

For example, a tablet can be prepared by compression or moldingtechniques, optionally, using one or more accessory ingredients.Compressed tablets can be prepared by compressing the active ingredientin a suitable machine into a free-flowing form, such as a powder orgranules. Thereafter, the compressed, free-flowing form optionally canbe mixed with a binders, diluents, lubricants, disintegrating agents,effervescing agents, dyestuffs, sweeteners, wetting agents, andnon-toxic and pharmacologically inactive substances typically present inpharmaceutical compositions. Molded tablets can be made by molding amixture of the powdered compound moistened with an inert liquid diluentin a suitable machine.

Suitable binders for use in the pharmaceutical preparation include, forexample, starches, gelatine, methylcellulose, gum arabic, tragacanth,and polyvinylpyrrolidone. Suitable diluents for use in thepharmaceutical preparation include, for example, lactose, dextrose,sucrose, mannitol, sorbitol, and cellulose. Suitable lubricants for usein the pharmaceutical preparation include, for example, silica, talc,stearic acid, magnesium or calcium stearate, and or polyethyleneglycols. Suitable disintegrating agents for use in the pharmaceuticalpreparation include, for example, starches, alginic acid, and alginates.Suitable wetting agents for use in the pharmaceutical preparationinclude, for example, lecithin, polysorbates, and laurylsulfates.Generally, any effervescing agents, dyestuffs, and/or sweeteners knownby those of ordinary skill in the art can be used in the preparation ofa pharmaceutical composition.

Desirably, daily dose of the composition (e.g., tablet, sachet, orcapsule) contains from about 0.1 to about 10 mg of optically pure (S,S)reboxetine, and is substantially free of its (R,R) stereoisomer. Morepreferably, each dose of the composite contains about 0.5 to about 8 mgof the active ingredient, optically-pure (S,S) reboxetine, and issubstantially free of its (R,R) stereoisomer. Even more preferably,however, each dose contains from about 0.5 to about 5 mg of the activeingredient, such as an optically-pure (S,S) reboxetine, and issubstantially free of its (R,R) stereoisomer. This dosage form permitsthe full daily dosage of about 0.5 to about 2.5 mg to be administered inone or two oral doses. This will allow for tablets containing 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,1.7, 1.8, 1.9. 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 mg of optically pure(S,S) reboxetine.

In another embodiment, a preferred daily dose of the composition (e.g.,tablet, sachet, or capsule) contains from about 0.1 to about 0.9 mg ofoptically pure (S,S) reboxetine, and is substantially free of its (R,R)stereoisomer. More preferably, each dose of the composition containsabout 0.5 to about 0.8 mg of the active ingredient, optically-pure (S,S)reboxetine, and is substantially free of its (R,R) stereoisomer. Evenmore preferably, however, each dose contains from about 0.5 to about0.75 mg of the active ingredient, optically pure (S,S) reboxetine, andis substantially free of its (R,R) stereoisomer. This dosage formpermits the full daily dosage of about 0.5 to about 0.9 mg to beadministered in one oral dose.

Patients suffering from depression, nicotine addiction, conductdisorder, oppositional defiant disorder, and/or attention-deficithyperactivity disorder will benefit from the administration of theinventive composition, and specifically one containing an optically pure(S,S) reboxetine, regardless of these or other co-morbid conditions.Diagnostic criteria for these disorders generally are provided by theAmerican Psychiatric Association and published in their “Diagnostic andStatistical Manual of Mental Disorders,” 4th ed. rev. (Washington D.C.1994), and in International Publication Nos. WO 99/15177, WO 99/15176,and WO 99/15163, the disclosures of which are hereby incorporated byreference.

Furthermore, patients suffering from addictive disorders and withdrawalsyndromes, adjustment disorders, apathy, attention-deficit hyperactivitydisorder, attention-deficit disorders due to medical conditions, bulimianervosa, chronic fatigue syndrome, chronic or acute stress, depression,dysthymic disorder, generalized anxiety disorder (GAD), nicotineaddiction, panic disorder, post-traumatic stress disorder, premenstrualdysphoric disorder, schizoaffective disorder, and SSRI “poop out”syndrome will benefit from the administration of the inventivecomposition, and specifically one containing optically pure (S,S)reboxetine.

These disorders display similar patterns in children, adolescents, andadults. Hence, methods of the present invention are effective in thetreatment of child, adolescent, and adult patients. For purposes of thepresent invention, a child is considered to be a person below the age ofpuberty, an adolescent is considered to be a person between the age ofpuberty and up to about 18 years of age, and an adult generally is aperson of at least about 18 years of age. As previously noted, theoptimum daily dosage for each patient must be determined by a treatingphysician taking into account each patient's size, other medicationswhich the patient is taking, identity and severity of the disorder, andall of the other circumstances of the patient.

As stated above, reboxetine acts as an antidepressant. Reboxetine,however, does not act like most antidepressants. Unlike trycyclicantidepressants, and even selective serotonin reuptake inhibitors(SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test,indicating that reboxetine is not a selective serotonin reuptakeinhibitor. Rather, reboxetine is selective for the noradrenergic system.Reboxetine is not an SSRI, but is a novel, selective, noradrenalincreuptake inhibitor (NRI). B. Leonard, “Noradrenaline in basic models ofdepression.” European-Neuropsychopharmacol, 7 Suppl. 1 pp. S11-6 andS71-3 (April, 1997). Unlike most prior generation drugs, reboxetine is ahighly selective norepinephrine reuptake inhibitor, with only marginalserotonin and no dopamine reuptake inhibitory activity. Reboxetinedisplays no anticholinergic binding activity in different animal models,and is devoid of monoamine oxidase (MAO) inhibitory activity.

Reboxetine also is a highly potent, pharmacologically specific, and fastacting agent. Investigations indicate that reboxetine has potentantireserpine activity, and combines the inhibitory properties ofclassical tricyclic antidepressants on the reuptake of noradrenalinewith an ability to desensitize β-adrenergic receptor function, withoutshowing any appreciable blocking action at muscarinic, cholinergic,histaminergic, and α-adrenergic receptors. Moreover, reboxetine showsless vagolytic activity than tricyclic antidepressants, and no evidenceof cardiotoxicity.

Accordingly, in another embodiment of the invention, racemic reboxetinecan be used to treat or prevent a number of mental and neurologicaldisorders. Specifically, reboxetine has been found particularly usefulfor treating or enhancing the treatment or prevention of a variety ofpsychiatric symptoms or disorders, with greater efficacy and with fewerside effects than with treatment by known drugs. Furthermore, reboxetinemay also be used to treat, or to enhance the treatment or prevention of,other specific psychiatric symptoms or disorders.

Mental and neurological disorders that may be treated or prevented byadministration of a therapeutically effective amount of a racemicreboxetine (or a derivative or pharmaceutically acceptable saltsthereof) include, but are not limited to adjustment disorders (includingdepressed mood, anxiety, mixed anxiety and depressed mood, disturbanceof conduct, and mixed disturbance of conduct and mood), age-associatedlearning and mental disorders (including Alzheimer's disease), anorexianervosa, apathy, attention-deficit (or other cognitive) disorders due togeneral medical conditions, bipolar disorder, bulimia nervosa, chronicfatigue syndrome, chronic or acute stress, chronic pain, cyclothymicdisorder, dysthymic disorder, fibromyalgia and other somatoformdisorders (including somatization disorder, conversion disorder, paindisorder, hypochondriasis, body dysmorphic disorder, undifferentiatedsomatoform disorder, and somatoform NOS), incontinence (i.e., stressincontinence, genuine stress incontinence, and mixed incontinence),mania, migraine headaches, obesity (i.e., reducing the weight of obeseor overweight patients), peripheral neuropathy, post-traumatic stressdisorder, premenstrual dysphoric disorder (i.e., premenstrual syndromeand late luteal phase dysphoric disorder), psychotic disorders(including schizophrenia, schizoaffective and schizophreniformdisorders), seasonal affective disorder, sleep disorders (such asnarcolepsy and enuresis), specific developmental disorders, selectiveserotonin reuptake inhibition (SSRI) “poop out” syndrome, and TICdisorders (e.g., Tourette's Disease).

Similar to (S,S) reboxetine, racemic reboxetine also can be used totreat humans suffering from migraine headaches, particularly to reducethe frequency, duration, intensity, and or complications resulting frommigraine headaches. Furthermore, racemic reboxetine can be used toprevent migraine headaches.

Additionally, racemic reboxetine can be used to treat incontinence(i.e., stress incontinence, genuine stress incontinence, and mixedincontinence). Stress urinary incontinence is a symptom describinginvoluntary loss of urine on carrying out any activity that raisesintra-abdominal pressure such as coughing or sneezing. Stressincontinence is also a clinical sign, that is the observation by a caregiver of a jet of urine escaping from the urethral meatus (opening) whenthe patient coughs or strains. Genuine Stress Incontinence is thepathological diagnosis of an incompetent urethral sphincter as diagnosedby Urodynamic testing. Mixed incontinence is stress incontinence incombination with urge incontinence. The latter is a part of the symptomcomplex of the Overative Bladder. Retention may be due to outflowobstruction (e.g., high urethral pressure), poor detrusor (bladdermuscle) contractility or lack of coordination between detrusorcontraction and urethral relaxation.

The racemate form of reboxetine is well tolerated and has a wide safetyrange. Racemic reboxetine can be administered to an individual in anamount in a range of about 2 to about 20 milligrams per patient per day(mg/day), and preferably about 4 to about 10 mg/day, and more preferablyabout 6 to about 10 mg/day. Depending upon the formulation and theindividual's disorder, the total daily dosage can be administered insmall amounts up to two times a day. Reboxetine typically isadministered orally, for example, in the form of tablets, but can beadministered parentally, transdermally, rectally, or vaginally.

A preferred method of administering racemic reboxetine is oral dosingonce or twice a day. It can also be administered at dosages of about 2,4, 6, 8, 10, or 12 mg/day or fractions thereof. For example, suitableadministrations could be about 4 mg in the morning and about 2 or about4 mg in the afternoon or evening. In some patients, the ideal dosingwould be about 3 to about 5 mg in the morning and about 3 to about 5 mgin the afternoon. A skilled physician or psychiatrist can determine theprecise level of dosing. The ideal dosing is routinely determined by anevaluation of clinical trials and the needs of specific patients.

In accordance with the present invention, the racemic reboxetine alsocan be administered as the free base or a pharmaceutically acceptablesalt thereof. The phrases “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to salts prepared frompharmaceutically acceptable acids or bases, including organic andinorganic acids and bases as described above with respect to the saltsof optically pure (S,S) reboxetine. A preferred pharmaceutical salt ofreboxetine is methanesulfonate (i.e., mesylate), which is prepared usingmethanesulfonic acid.

Treatment or prevention of above disorders involves the administrationof reboxetine in a manner and form that result in a reduction in thesymptoms of the disease or disorder. Typically, the symptoms exhibitedby children, adolescents, and adults are similar to each other. Hence,as noted above, methods of the present invention are effective in thetreatment of child, adolescent, and adult patients.

EXAMPLE

This example demonstrates the superior pharmacological selectivity andpotency of a composition according to the present invention. Morespecifically, this example demonstrates the superior pharmacologicalselectivity and potency of (S,S) reboxetine compared to its (R,R)stereoisomer and to racemic reboxetine.

Sprague-Dawley rats weighing about 250 to about 300 grams (g) weredecapitated, and cerebral cortical tissue was removed immediately.Cerebral cortices were homogenized in nine volumes of medium eachcontaining 0.32 molar (M) sucrose using a rotating pestle. The obtainedhomogenate was centrifuged at about 1000×g for about 10 minutes at about4° C. A supernatant was collected and further centrifuged at about20,000×g for about 20 minutes at a temperature of about 4° C. A proteinpellet resulting from the centrifuge steps was re-suspended in aKreb's-Hepes buffer to result in a protein concentration of about 2mg/ml of buffer. The buffer was maintained at a pH of about 7.0 andcontained: 20 mM Hepes; 4.16 mM NaHCO₃; 0.44 mM KH₂PO₄; 0.63 mM NaH₂PO₄;127 mM NaCl; 5.36 mM KCl; 1.26 mM CaCl₂; and 0.98 mM MgCl₂.

Protein/buffer suspension was introduced into 166 assay tubes such thatabout 30 μg (10⁶ grams) to about 150 μg of the protein was added to eachof 166 assay tubes (i.e., 80 assays per transporter assay). Binding toserotonin and norepinephrine reuptake sites was determined as follows.Synaptosomal uptake of ³H-norpinephrine was determined as follows. About1.4 nanomolar of [³H]citalopram and about 1.9 nM of [³H]nisoxetine wereused to label serotonin and norepinephrine reuptake sites, respectively.Nonspecific binding was defined by 100 micromolar (μM) fluoxetine (forserotonin) and 10 μM desipramine (for norepinephrine). Incubation intotal assay volume of about 500 microliters (μl) was carried out forabout 60 minutes (for serotonin) and 120 minutes (for norepinephrine).Both incubations were carried out at about 25 ° C., and terminated byrapid filtration through a 48-well cell harvester though GFB filters(pre-soaked with about 0.5 PEI for about 4 hours) in a 3×5 ml ofice-cold 200 mM tris-HCl, pH 7.0. Punched-out filters were placed into 7ml minivials and radioactive assayed by liquid scintillation counting.

The ability of reboxetine (i.e., racemic mixture of (R,R) and (S,S)reboxetine), (R,R) reboxetine, and (S,S) reboxetine to bind tonorepinephrine and serotonin reuptake sites was evaluated in bindingassays using the two radioligands, [³H]citalopram and [³H]nisoxetine.The concentration of the test compound required to inhibit 50% of thespecific binding at the two reuptake sites (IC₅₀ values) were determinedby non-linear least square regression analysis. A conversion of IC₅₀values to K_(i) values was performed using the Cheng-Prassoff equationpresented below:

K _(i) =IC ₅₀/(1+([L]/[K _(d)of L])),

wherein [L] is the radioligand concentration used in nM, and K_(d) isthe binding affinity of L in nM. See Y. C. Cheng and W. H. Prusoff,“Relationship Between the Inhibitory Constant (K_(i)) and theConcentration of Inhibitor Which Causes 50% Inhibition (IC₅₀) of anEnzymatic Reaction,” Biochemical Pharmacology, vol. 22, pp. 3099-3108(1973).

The K_(i) values calculated according to the Cheng-Prassoff equation areprovided in the table below:

TABLE Norepinephrine Serotonin Selectivity of K_(i) of Reuptake ReuptakeSerotonin/ Compound (K_(i) nM) (K_(i) nM) Norepinphrine (S,S) Reboxetine0.23 ± 0.06 2937 ± 246 12,770 (R,R) 7.0 ± 1.7 104 ± 43 15 ReboxetineReboxetine 1.6 ± 0.6 129 ± 13 81

The data shows that (S,S) reboxetine is about five to about eight foldmore potent than the reboxetine racemate with respect to inhibiting thereuptake of norepinephrine. In addition, racemic reboxetine has an 81fold selectivity favoring norepinephrine reuptake inhibition overserontonin reuptake inhibition. Unexpectedly, the enantiomericselectivity of the (S,S) and (R,R) reboxetine stereoisomers with respectto inhibiting the reuptake of norepinephrine and serotonin are quitedifferent. The (S,S) enantiomer is very poor with respect to inhibitingreuptake of serotonin (i.e., a high K_(i)) and, therefore, has asurprisingly high selectivity for the norepinephrine reuptake site. Inparticular, the selectivity of serotonin versus norepinephrine increasesfrom 81 (for the racemate) to 12,770 for an optically pure (S,S)reboxetine. Accordingly, administration of a therapeutic dose of (S,S)reboxetine effectively inhibits nonepinephrine reuptake, but serotoninreuptake essentially is not affected. Likewise, there is a furtherincrease in separation between the action on norepinephrine reuptakesites and at other receptors. As a consequence, adverse side effectsassociated with the inhibition of serotonin reuptake and blockade atother receptors are not manifested.

Surprisingly, this effect is not observed with (R,R) reboxetine, but arequite to the contrary. (R,R) reboxetine is a weaker inhibitor than (S,S)reboxetine with respect to nonepinphrine reuptake, i.e., affinity(K_(i)) for (R,R) reboxetine is 7 nM whereas the K_(i) for (S,S)reboxetine is 0.23 nM. In addition, (R, R) reboxetine is much moreeffective at inhibiting serotonin uptake than (S,S) reboxetine, i.e.,K_(i) for (R,R) reboxetine is 104 nM, whereas the K_(i) for (S,S)reboxetine is 2937 nM. Accordingly, (R,R) reboxetine has a lowselectivity for nonepinephrine reuptake inhibition versus serotoninreuptake inhibition.

The surprisingly high potency of the (S,S) enantiomer over both theracemic reboxetine and (R,R) reboxetine provides a treating physician anability to prescribe an effective dosage of a norepinephrine reuptakeinhibitor, i.e., (S,S) reboxetine, that is about 10% to about 20% of thecurrent daily dosage of reboxetine (racemate) to achieve the samereuptake inhibition at the norepinephrine site. In addition, thesurprisingly high inhibition selectivity of an optically pure (S,S)reboxetine essentially limits inhibition to norepinephrine reuptake,thereby reducing adverse side effects associated with inhibition atserotonin reuptake sites and blockade at other receptors.

The foregoing description is given for clearness of understanding only,and no unnecessary limitations should be understood therefrom, asmodifications within the scope of the invention may be apparent to thosehaving ordinary skill in the art.

What is claimed is:
 1. A method of treating an individual suffering frommigraine headaches, the method comprising the step of administering tothe individual a therapeutically effective amount of a compositioncomprising a compound having a pharmacological selectivity of serotonin(K_(i))/norepinephrine (K_(i)) of at least about
 5000. 2. The method ofclaim 1 wherein said composition is administered in an amount of about0.1 to about 10 mg/day.
 3. The method of claim 2 wherein saidcomposition is administered in an amount of about 0.5 to about 8 mg/day.4. The method of claim 3 wherein said composition is administered in anamount of about 0.5 to about 5 mg/day.
 5. The method of claim 4 whereinsaid composition is administered in an amount of about 0.5 to about 2.5mg/day.
 6. The method of claim 5 wherein said composition isadministered in an amount of about 0.5 to about 0.9 mg/day.
 7. Themethod of claim 6 wherein said composition is administered in an amountof about 0.5 to about 0.8 mg/day.
 8. The method of claim 7 wherein saidcomposition is administered in an amount of about 0.5 to about 0.75mg/day.
 9. The method of claim 1 wherein said composition isadministered orally, topically, parenterally, transdermally, rectally,or vaginally.
 10. The method of claim 9 wherein said composition isorally administered, and further comprising a pharmaceuticallyacceptable carrier selected from the group consisting of a binder,diluent, lubricant, disintegrating agent, effervescing agent, dyestuff,sweetener, wetting agent, and mixtures thereof.
 11. The method of claim10 wherein the oral administration is by a sachet, capsule, tablet, oraerosol spray.
 12. The method of claim 9 wherein said composition isparenterally administered subcutaneously, intraveously, orintramuscularly.
 13. The method of claim 1 wherein said compoundcomprises an optically pure (S,S) reboxetine, or a pharmaceuticallyacceptable salt thereof, said compound being substantially free of (R,R)reboxetine.
 14. The method of claim 13 wherein the pharmaceuticallyacceptable salt is a methanesulfonate salt.
 15. The method of claim 13wherein the optically pure (S,S) reboxetine or pharmaceuticallyacceptable salt thereof comprises at least about 90 wt. % of (S,S)reboxetine, and less than about 10 wt. % of (R,R) reboxetine, based onthe total weight of the (S,S) and (R,R) reboxetine present.
 16. Themethod of claim 15 wherein the optically pure (S,S) reboxetine orpharmaceutically acceptable salt thereof comprises at least about 97 wt.% of (S,S) reboxetine and less than about 3 wt. % of (R,R) reboxetine,based on the total weight of the (S,S) and (R,R) reboxetine present. 17.The method of claim 16 wherein the optically pure (S,S) reboxetine orpharmaceutically acceptable salt thereof comprises at least about 99 wt.% of (S,S) reboxetine and less than about 1 wt. % of (R,R) reboxetine,based on the total weight of the (S,S) and (R,R) reboxetine present. 18.The method of claim 1 wherein the compound has a pharmacologicalselectivity of serotonin (K_(i))/norepinephrine (K_(i)) of at leastabout 10,000.
 19. The method of claim 18 wherein the compound has apharmacological selectivity of serotonin (K_(i))/norepinephrine (K_(i))of at least about 12,000.
 20. The method of claim 19 wherein thecompound has a pharmacological selectivity of serotonin(K_(i))/norepinephrine (K_(i)) of at least about 25,000.
 21. The methodof claim 20 wherein the compound has a pharmacological selectivity ofserotonin (K_(i))/norepinephrine (K_(i)) of at least about 50,000. 22.The method of claim 21 wherein the compound has a pharmacologicalselectivity of serotonin (K_(i))/norepinephrine (K_(i)) of at leastabout 75,000.
 23. The method of claim 22 wherein the compound has apharmacological selectivity of serotonin (K_(i))/norepinephrine (K_(i))of at least about 100,000.
 24. A method of treating an individualsuffering from migraine headaches while diminishing adverse sideeffects, the method comprising the step of administering to theindividual a total dose of about 0.1 to about 10 mg/day of an opticallypure (S,S) reboxetine, or a pharmaceutically acceptable salt thereof,said optically pure (S,S) reboxetine being substantially free of (R,R)reboxetine.
 25. The method of claim 24 wherein said adverse side effectscomprise dizziness, insomnia, lightheadedness, changes in bloodpressure, sweating, gastrointestinal disturbances, sexual dysfunction inmales, anticholinergic-like effects, and side effects with drug-druginteractions.
 26. The method of claim 24 wherein said composition isadministered In an amount of about 0.5 to about 8 mg/day.
 27. The methodof claim 26 wherein said composition is administered in an amount ofabout 0.5 to about 5 mg/day.
 28. The method of claim 27 wherein saidcomposition is administered in an amount about 0.5 about 2.5 mg/day. 29.The method of claim 28 wherein said composition is administered in anamount of about 0.5 to about 0.9 mg/day.
 30. The method of claim 29wherein said composition is administered in amount of about 0.5 to about0.8 mg/day.
 31. The method of claim 28 wherein said composition isadministered In an amount of about 0.5 to about 0.75 gm/day.
 32. Themethod of claim 26 wherein said composition is administered orally,topically, parenterally transdermally. rectally, or vaginally.
 33. Themethod of claim 32 wherein said composition is orally administered, andfurther comprising a pharmaceutically acceptable carrier selected fromthe group consisting of a binder, diluent, lubricant, disintegratingagent, effervescing agent, dyestuff, sweetener, wetting agent, aridmixtures thereof.
 34. The method of claim 33 wherein the oraladministration is by a sachet, capsule, tablet, or aerosol spray. 35.The method of claim 32 wherein said composition is parenterallyadministered subcutaneously, intraveously, or intramuscularly.
 36. Themethod of claim 26 wherein the pharmaceutically acceptable salt is amethanesulfonate salt.
 37. The method of claim 26 wherein the opticallypure (S,S) reboxetine or pharmaceutically acceptable spit thereofcomprises at least about 90 wt. % of (S,S) reboxetine, and less thanabout 10 wt % of (R,R) reboxetine, based on the total weight of the(S,S) (R,R) reboxetine present.
 38. The method of claim 37 wherein theoptically pure (S,S) reboxetine or pharmaceutically acceptable saltthereof comprises at least about 97 wt. % of (S,S) reboxetine and lessthan about 3 wt. % of (R,R) reboxetine, based on the total weight of the(S,S) and (R,R) reboxetine present.
 39. The method claim 38 wherein theoptically pure (S,S) reboxetine or pharmaceutically acceptable saltThereof comprises at least about 99 wt. % of (S,S) reboxetine and lessthan about 1 wt. % of (R,R) reboxetine, based on the total weight of the(S,S) ant (R,R) reboxetine present.